Bridging past and future: the evolution of genetic diagnosis in FSHD and the role of emerging technologies in a globalized framework

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder characterized by marked clinical and molecular heterogeneity. Over more than two decades, molecular diagnosis has relied on Southern blotting to resolve the complex D4Z4 macrosatellite at chromosome 4q35. While this approach remains a reference standard, its technical constraints and the need for complementary layers of information have become more evident as FSHD diagnostics is increasingly required to support patient stratification, genotype-phenotype correlation, and clinical trial readiness. In this context, the review traces the evolution of FSHD diagnostics from classical molecular approaches to modern genome-scale technologies that enable direct characterization of the D4Z4 locus, improve interpretation of borderline and atypical cases, and support integrated diagnostic workflows. Beyond technical innovation, the review highlights the growing need for harmonized diagnostic algorithms, international collaboration, and federated data infrastructures to support consistent interpretation across populations and healthcare systems. It further emphasizes how emerging requirements for molecular stratification in clinical trials, together with persistent global disparities in access to genetic testing, are reshaping priorities in FSHD diagnostics, positioning FSHD as a model for how rare disease diagnostics can integrate classical expertise with next-generation technologies to support clinical care, trial readiness, and more equitable access to diagnosis worldwide.